1. Technical Field
The present invention relates to N-(pyrazolylmethyl)arylsulfonamide derivatives useful as calcium ion channel blockers, pharmaceutically acceptable salts thereof, and the medicinal use thereof as therapeutic agents using their calcium ion channel blocking effect.
2. Background Art
Voltage-gated calcium ion channels play an important role in intracellular signal transmission by increasing calcium inflow to cells in response to neural stimuli. These calcium channels are classified as high-voltage activated calcium channels and low-voltage activated calcium channels. Representative among low-voltage activated calcium channels are T-type calcium channels.
T-type calcium ion channels are found in central muscles, endocrine glands in the adrenal, sinoatrial node, heart, etc. T-type calcium channel antagonists are known to exert therapeutic effects on cerebral and cardiac diseases such as epilepsy, hypertension, angina pectoris, etc. [1) Hosravani, Houman et al., “Effects of Cav3.2 channel mutations linked to idiopathic generalized epilepsy”, Annals of Neurology (2005), 57 (5), 745-749; 2) Vitko, Iuliia et al., “Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel”, Journal of Neuroscience (2005), 25 (19), 4844-4855; 3) Clozel, Cardiovas Drugs Ther. (1990), 4, pp. 731-736; 4) Hefti, Arzneimittelforschung (1990), 40, 417-421; 5) Moosmang, Sven et al., “Antihypertensive Effects of the Putative T-Type Calcium Channel Antagonist Mibefradil Are Mediated by the L-Type Calcium Channel Cav1. 2”, Circulation Research (2006), 98 (1), 105-110].
T-type calcium channels are also involved in cancer cell growth, and T-type calcium channel blockers are reported to be useful as anti-cancer agents inhibiting cancer cell growth [“Functional role of T-type calcium channel in tumor growth and progression: prospective in cancer therapy” British Journal of Pharmacology, (2012), 166, 1244-1246].
In addition, recent reports have disclosed therapeutic effects of T-type calcium ion channel blockers on pain. Briefly, Mibefradil and Ethosuximide, both known as T-type calcium ion channel antagonists, were reported to reverse mechanical and thermal pain induction dose-dependently in a spinal nerve ligation animal model, demonstrating that the T-type calcium ion channel antagonists have a therapeutic effect on neuropathic pain [Dogrul, Ahmet et al., “Reversal of experimental neuropathic pain by T-type calcium channel blockers”, Pain, 2003, 105, 159-168].
Mibefradil, developed as a T-type calcium ion channel antagonist (Mibefradil, Ro 40-5967, WO 98/49149), was used to treat hypertension and angina pectoris, but was withdrawn from the market due to the unfavorable drug-drug interaction caused by cytochromes P-450 3A4 and 2D6. Substantially no drugs are available as T-type calcium ion channel blockers, and therefore the need for the development of a novel T-type calcium ion channel blocker is urgent.
WO 2005/073197 discloses derivatives of N′-(1,5-diphenyl-1H-pyrazol-3-yl)sulfonamide, represented by the following Chemical Formula A:

In this patent document, the compound of Chemical Formula A is demonstrated to have antagonistic activity against the cannabinoid receptor type 1 (CB1), and described to be useful for the treatment of appetite disorders, gastric disorders, inflammations, immune system diseases, psychotic disorders, alcohol dependence, and nicotine dependence.
Leading to the present invention, intensive and thorough research into the development of novel compounds acting on calcium ion channels was carried out, and was found that novel N-(pyrazolylmethyl)arylsulfonamide derivatives exhibit excellent antagonistic activity against T-type calcium ion channels. The novel compounds of the present invention, which have a substituted or unsubstituted phenyl group at either N1 or C5 position of the pyrazole ring moiety, and an alkyl group at the position, not occupied by the phenyl group, exhibit excellent antagonistic activity against T-type calcium ion channels.